My lab studies how organisms defend against environmental and metabolic stresses, and how these stress defenses influence aging. We use the nematode C. elegans as a model organism, and most of our projects are centered on the transcription regulator SKN-1/Nrf, which orchestrates a conserved response to oxidative stress and reactive toxins. SKN-1/Nrf activates detoxification genes, promotes longevity, and is required for normal lifespan and oxidative stress resistance. Our more recent work has implicated SKN-1/Nrf in a surprisingly broad spectrum of other stress defense and homeostasis functions, including maintenance of proteasome function, the extracellular matrix, ER homeostasis, and lipid metabolism. One important goal is to elucidate how signals and cooperating factors modulate SKN-1/Nrf function so it can perform such a wide variety of functions. Another is to understand the involvement of these protective processes in determining lifespan.

We also want to understand how stress response factors such as SKN-1/Nrf are regulated in response to different stress and metabolic stimuli. We have found that SKN-1/Nrf is inhibited directly by insulin/IGF-1 signaling (IIS), and is important for the increased stress-resistance and longevity seen when IIS is reduced. We have also determined that SKN-1/Nrf responds to perturbations in protein synthesis, and is critical in relationships between growth signals, protein synthesis, and aging. This is particularly important in the context of the mTOR (mechanistic Target of Rapamycin) pathways, which are central to growth regulation. Both mTOR pathways (mTORC1 and mTORC2) regulate SKN-1/Nrf, and the lifespan extensions associated with suppression of either pathway depend upon SKN-1/Nrf. We have identified a mode of signaling from the ER that is critical for SKN-1 function, and seems to integrate ER and cytoplasmic homeostasis. We are applying the advantages of C. elegans to expand our understanding of how SKN-1/Nrf proteins function and promote longevity, and of mechanisms through which they and other stress defenses are regulated under normal and adverse conditions.